Diesterphosphiteamides of aminoacid derivatives



Patented Mar. 30, 1954 DIESTERPHO SPHITEAMIDES F AMINOACID DERIVATIVES George W. Anderson, Darien, Conn, assignor to American Cyanamid Company, New York, N. Y.,

a corporation of Maine i No Drawing. Application December 1, 1950,

Serial No. 198,730

This invention relates to new organic compounds of phosphorus and methods of making the same. More particularly the invention relates to new diesterphosphiteamides of aminoacid derivatives.

An object of the invention is to make available a new class or" organic compounds useful, for instance, as intermediates in the production of valuable solvents for paints, paint removers, paint 2 the specification and claimsas halophosphites; or as diesters. of phosphorous halides. Because of the easeof preparation and reaction velocity, the chlorophosphites. are the preferred halophos- 'phites.

The aminoacid' derivatives suitable for the process of this invention are prepared from an aminoacid having amine hydrogen by blocking the carboxy groups. The procedure of blocking:

brush cleaners, antioxidants, and reducing a reactive group is well known in the art and, in agents. The new class of compounds is also usethe case of carboxy groups, may be done by iul as intermediates in the preparation of amides esterification, or the equivalent; Examples of or peptides as disclosed. inmy co-pending appliaminoacids, the derivatives of which are suit.- cation, S. N. 198,729, new Paten NO- ,617,794, able, are as follows: aromatic aminoacids such filed concurrently herewith. Another obiect of as the invention is to provide suitable processes for the preparation of the new compounds. Other NH2 CGH4 COOH HOOC C6H3C1 NH CH3 objects will appear hereinafter. and the like; aliphatic aminoacids such as The new diesterphosphiteamides of aminoacid derivatives of this invention, which are also referred to simply as aminophosphites, may he T figlrreulipecifically illustrated by the following HOOC CH2 NH CH2 COOH O R, HOOC-CH (NH2) (CH2) 4-NH2 ZNMP/ and the like; alicyclic aminoacids such as HOOC-CsI-I10NH2 and the like; heterocyclic aminoacids such as 3-pyrrolidinecarboxylic acid in which ZN is a radical derived from an aminoand the like. Derivatives of many other aminoacid derivative and, in which R and R" are the acids are equally satisfactory and in fact, the same or different non-functional organic radionly critical requirements of the aminoacid decals. rivative is that it have amine hydrogen and have By non-functional organic radical, it is meant a basic dissociation constant greater than an organic radical used simply for the purpose of 1 10 at 25 C; esterification and one which does not enter into The new compounds and process of this inh r i n whereby the phosphi e is pr volition are of particular interest when a derivap ared, does not react with the aminophosp hite tive of an 'aminoacid having an asymmetric carafter it is prepared and the variation of which bon atom is employed, such as esters of the 3 does not appreciably affect the chemical propernaturally occurring alpha aminoacids. Illustraties of the ami ohho p EXa-mllles of s c tive of the naturally occurring alpha aminoacids a radicals are: alkyl such as ethyl, propyl, butyl, 40 the derivatives of which are of particular interest octyl, and the like; aromatic such as phenyl, in connection with the process of this invention t napthyl, tolyl, and the like; etc. It is believed are derivatives of the following: alanine, valine,

that one skilled in the art of organic synthesis norvaline, leuoine, norleucine, isoleucine, isowill have little difliculty selecting suitableradicals valine, phenylalanine, tyrosine, serine, cysteine, for R and B". 4-5 methionine, aspartic acid, glutamic acid, lysine, The new compounds of this invention may conornithine, asparagine, citrulline, histidine, tryptorveniently be prepared by reacting an aminoacid phane, proline, hydroxyproline. Generally speakderivative having amine hydrogen with a coing' the naturally occurring aminoacids such as. pound such as represented by the formula: the above are alpha aminoacids having fromtwo to twelve carbon atoms. If the aminophosphites: are prepared; from aminoacid derivatives having more than. one;

functioning group, i. e., groups-:having active hywhere X is halogen and R and R" are as dew drogen, enough halophosphite. may, if. desired, fined above. These compoundsare referred to in beemployedtoreactwith alliof the activegroups:

however, it is possible to use only one molecular equivalent of the halophosphite to form aminophosphites in which the radical represented by ZN in the general formula has other functioning groups. For instance, the monoaminophosphite of a diamine may be formed in this manner. Aminophosphites in which the radical represented by ZN in the general formula does contain a functioning group decompose at somewhat lower temperatures than otherwise because of an interaction of the functioning group with the aminophosphite itself, and if the aminophosphite is to be used as an intermediate, it is advisable to temporarily block the second functioning group of the aminoacid derivative by acylation before making the aminophosphite.

The reaction is conveniently performed in an anhydrous, inert, organic solvent. Examples of suitable solvents are: benzene, toluene, xylene or other aromatic hydrocarbons; chloroform or other halogenated aliphatics; normal octane or other aliphatic hydrocarbons; cyclohexane or other alicyclic hydrocarbon solvents; ethyl acetate or other of the lower aliphatic esters; ethyl ether or other lower aliphatic ethers; methyl butyl ketone or other lower aliphatic ketones; dioxane or other cyclic e ers, etc. Choice of solvent will depend princr ly upon convenience, but as the new class of compounds are useful primarily as intermediates, in many instances they may be utilized without isolation from the solvent and in such instances the intended use will affect the choice of solvent.

As halogen acid is formed during the reaction which tends to react with the free amine reactant, it is usually advantageous to have a halogen acid acceptor present in the reaction mixture. The preferred halogen acid acceptors are the tertiary amines such as triethylamine, tributylamine and the like.

The reaction proceeds readily at room temperature or at any other temperature below the decomposition temperature of the reaction product. As a matter of convenience one is usually limited to a range between the freezing and reflux temperatures of the solvent employed. Temperatures between C. and 50 C. are preferred.

The reaction proceeds immediately upon mixing the two reactants as is evidenced, when a tertiary amine is present as a halogen acid ac- Example I Diethyl chlorophosphite (3.30 g.) is dissolved in about 25 cc. of anhydrous ether. The solution is chilled by means of an ice water bath and to the chilled solution is added 8.0 g. of DL- phenylalanine ethyl ester. After allowing the mixture to warm to room temperature, the precipitated DL-phenylalanine ethyl ester hydrochloride is removed by filtration. The ether solvent is removed by distillation and diethyl-@- carbethoxy 8 phenylethylaminophosphite obtained as a colorless oil; boiling point about 145 4 C. at 0.2 mm. of mercury pressure; refractive index n :1.4911. The calculated phosphorus content of this compound is 9.88%; found by analysis, 9.67%.

Example II To about 25 cc. of anhydrous other there is added .02 mole of diethyl chlorophosphite. The solution is chilled by means of an ice water bath and to the chilled solution is added .02 mole of Dir-phenylalanine ethyl ester and .02 mole of triethylamine. After allowing the mixture to warm to room temperature, the precipitate of triethylamine hydrochloride is removed by filtration, and the diethyl-u-carbethoxy-e-phenylethylaminophosphite obtained according to the procedure of Example I is equally good yield.

Example III Example II is repeated but employing .02 mole of DL-alanine ethyl ester in place of the DL- phenylalanine ethyl ester of Example II. The product, diethyla-carbethoxyethylaminophosphite, distills at 78 C., at about 0.15 mm. pressure and has a refractive index of n :l.435.

Example IV To about 25 cc. of anhydrous ether there is added .02 mole of DL-phenylalanine ethyl ester. The solution is chilled in an ice water bath and to the chilled solution is added .04 mole of triethylamine and .02 mole of dibutyl chlorophosphite. The precipitate of triethylamine hydrochloride is removed by filtration after allowing the mixture to warm to room temperature. Distillation of the ether solvent yields dibutyl-a-carbethoxy-[3phenylethylaminophosphite as an oil which distills at 97 C.-100 C. at about 0.3 mm. pressure and has a refractive index of Example V Example IV is repeated but using .02 mole of diphenyl chlorophosphite in place of the dibutyl chlorophosphite of Example IV. The product, diphenyl a carbethoxy c phenylethyl aminophosphite is a gummy liquid soluble in most organic solvents.

Example VI A suspension of 19.66 g. of glycylglycine ethyl ester hydrochloride in 200 cc. of anhydrous ether is chilled in an ice water bath. To the chilled solution is added 20.2 g. of triethylamine in 50 cc. of anhydrous ether. This is followed by the addition of 15.6 g. of diethyl chlorophosphite in 100 cc. of absolute ether over a period of five to ten minutes. The reaction mixture is allowed to warm to room temperature with stirring (approximately forty-five minutes). After filtering off the salts the other solution is distilled to obtain about 16.4 g. of the glycylglycine derivative as an oil.

I claim:

1. Diesterphosphiteamides of aminoacid derivatives represented by the formula:

wherein ZN represents a substituted amino radical having a blocked carboxyl group, and R and R represent hydrocarbon groups having not more than about 8 carbon atoms.

5 2. Diesterphosphiteamides of aminoacid amides represented by the formula:

ZN-P

OR wherein ZN represents a substituted amino radical having a carboxyl amide group and R and R are hydrocarbon groups having not more than about 8 carbon atoms.

3. Diesterphosphiteamides of peptide esters represented by the formula:

ZN-P

OR wherein ZN represents a substituted amino radical having a carboxyl ester group and at least one peptide linkage and R and R represent hydrocarbon groups having not more than about 8 carbon atoms.

4. The diethylphosphiteamide of glycylglycine ethyl ester.

5. The diesterphosphiteamides of aminopropionic acid esters represented by the formula:

000R" OR OHaCH-NHP wherein -COOR" represents a carboxyl ester group and R and R are hydrocarbon groups having not more than about 8 carbon atoms.

6. Diethyl alpha-carbethoxyethylaminophosphite.

7. Diesterphosphiteamides of alpha-aminobeta-phenylpropionic acid esters represented by the formula:

COOR" OR wherein COOR" represents a carboxyl ester group and R and R represent hydrocarbon groups having not more than about 8 carbon atoms.

8. Diethyl alpha carbethoxy beta phenylethylaminophosphite.

9. Diphenyl alpha carbethoxy-beta-phenylethylaminophosphite.

10. Dibutyl alpha carbethoxy beta-phenylethylaminophosphite.

11. A method of preparing diesterphosphiteamides represented by the formula:

OR ZN-P/ 6 wherein ZN represents a substituted amino radical having a blocked carboxyl group and R and R represent hydrocarbon groups having not more than about 8 carbon atoms, which comprises re- 13. The process of claim 11 wherein the aminoacid derivative is an ester of an optically active alpha-aminoacid.

14. A process of preparing diesterphosphiteamides of aminoacid esters represented by the formula:

/OR ZN-P wherein ZN represents a substituted amino radical having a carboxyl ester group and R and R are hydrocarbon groups having not more than about 8 carbon atoms, which comprises reacting,

in the presence of a tertiary amine and in an organic solvent, an aminoacid ester of an optically active alpha-aminoacid having amine hydrogen, said aminoacid ester having a basic dissociation constant greater than 1 10 at 25 0., with a diester of phosphorous acid chloride represented by the formula:

wherein R and R are as defined above.

15. The process of claim 14 when said diester of phosphorous acid chloride is diethylchlorophosphite.

GEORGE W. ANDERSON.

References Cited in the file of this patent Schechan: J. Am. Chem. 800.,

vol. 72, pages 1312-1316 (1950). 

1. DIESTERPHOSPHITEAMIDES OF AMINOACID DERIVATIVES REPRESENTED BY THE FORMULA:
 11. A METHOD OF PREPARING DIESTERPHOSPHITEAMIDES REPRESENTED BY THE FORMULA: 